Epidemiological studies show that only a minority of people exposed to addictive drugs develop addiction, suggesting that preexisting biological factors contribute to addiction vulnerability.Genome-wide association studies support this hypothesis by identifying genetic variants that are partially shared across different addictive drugs (Lai et al., 2026).Twin and family studies similarly indicate that addiction-related traits are heritable.For example, unaffected siblings of people with stimulant addiction show behavioral and neurobiological traits associated with addiction vulnerability, including impulsivity and impaired inhibitory control; these results suggest that inherited factors contribute to addiction risk even before drug exposure (Ersche et al., 2012).Although environmental influences and life experiences also contribute to addiction development, the biological mechanisms underlying vulnerability and resilience remain incompletely understood.One hypothesis is that individuals who develop addiction are biologically more sensitive to the rewarding effects of drugs.Human studies support this idea by showing that stronger stimulant and rewarding responses during initial drug exposure predict later drug use and addiction.For example, greater alcohol-induced stimulation, liking, and wanting in recreational drinkers predict future heavy alcohol use, and these positive subjective effects progressively increase in people who later develop alcohol addiction (King et al., 2025).Similarly, genetic polymorphisms can influence subjective drug responses.Variants of the μ-opioid receptor gene (OPRM1), including the A118G polymorphism, alter receptor signaling and are associated with differences in the subjective and reinforcing effects of opioids (Dunn et al., 2024).However, addiction vulnerability may depend not only on sensitivity to rewarding drug effects but also on sensitivity to aversive drug effects.Different addictive drugs produce negative subjective effects during initial exposure, including dysphoria, nausea, sedation, and conditioned aversion, which can influence subsequent drug use.Thus, heightened sensitivity to aversive drug effects may represent an inherited mechanism of resilience to addiction.Evidence for this idea comes from studies using selectively bred alcohol-preferring (P) rats.Across generations of selective breeding, these rats show reduced sensitivity to the aversive, ataxic, and hypothermic effects of alcohol compared with alcohol-nonpreferring (NP) rats while consuming large amounts of alcohol (Bell et al., 2006).These findings suggest that reduced sensitivity to alcohol's aversive effects increases vulnerability to alcohol addiction, whereas greater sensitivity may promote resilience.Like alcohol, cocaine produces both rewarding and aversive effects, and both people and lab animals differ in their sensitivity to these effects.However, over the last several decades, the role of cocaine's aversive effects in addiction has received relatively little attention in both human and animal research.One reason is that cocaine is a potent operant reinforcer that reliably supports self-administration in mice, rats, monkeys, and humans.In addition, standard operant self-administration procedures are not well suited for studying drug aversion.Cocaine aversive effects can be studied using the runway model and conditioned place preference/aversion (CPP/CPA) procedures (Ettenberg, 2009;Su et al., 2013).In the runway model, rodents traverse an alley to a goal box where they receive an appetitive stimulus such as drug infusions or palatable food or an aversive stimulus, such as footshock.In the CPP procedure, a reinforcer is paired with a specific context, while a different
D’Ottavio et al. (Mon,) studied this question.